Profiling the cancer-prone microenvironment in a zebrafish model for MPNST
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ABSTRACT:
PROVIDER: PRJNA814235 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18278271_1.fastq.gz | Fastqsanger.gz | |||
| SRR18278271_2.fastq.gz | Fastqsanger.gz | |||
| SRR18278272_1.fastq.gz | Fastqsanger.gz | |||
| SRR18278272_2.fastq.gz | Fastqsanger.gz | |||
| SRR18278273_1.fastq.gz | Fastqsanger.gz |
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Project description:Microenvironmental contributions to soft tissue sarcoma progression are relatively undefined, particularly in the context of sarcoma onset. Use of animal models to reveal these contributions is impeded by (1) the difficulty in discriminating between microenvironmental, precancerous, and cancer cells; and (2) the challenge in defining a precancerous microenvironment. We developed a zebrafish model that allows segregation of microenvironmental, precancerous, and cancerous cell populations by fluorescence-activated cell sorting. This model exhibits high predilection for malignant peripheral nerve sheath tumor (MPNST), a type of soft tissue sarcoma that exhibits rapid, aggressive growth. Using RNA-seq, we profiled the transcriptomes of microenvironmental cells from our zebrafish MPNST model. We show broad activation of inflammatory and immune-associated signaling networks and significant upregulation of tumor-promoting ligands in both precancerous and cancerous microenvironments. We also identify specific ligand-receptor pairs that may promote sarcomagenesis. This work provides insight into how the microenvironment may promote MPNST initiation and progression.
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Project description:Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma that lacks effective therapeutic strategies. By characterizing recurrent gene copy number aberrations, we gain insight into the most altered pathways with the purpose of scanning possible therapeutic targets. We conducted a microarray-based comparative genomic hybridization profiling of two cohorts of primary MPNST tissue samples including 25 patients treated at The University of Texas MD Anderson Cancer Center and 26 patients from Tianjin Cancer Hospital. All samples had at least 90% tumor content. Commercially available normal genomic DNAs were used as control.
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Project description:RNA Sequencing - Zebrafish FASD Model
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Project description:Aneuploidy is a hallmark of human cancers, but most mouse cancer models lack the extensive aneuploidy seen in many human tumors. The zebrafish is becoming an increasingly popular model for studying cancer. Here we report that malignant peripheral nerve sheath tumors (MPNSTs) that arise in zebrafish as a result of mutations in either ribosomal protein (rp) genes or in p53 are highly aneuploid. Karyotyping reveals that these tumors frequently harbor near-triploid numbers of chromosomes, and they vary in chromosome number from cell-to-cell within a single tumor. Using array CGH (aCGH) we found that, as in human cancers, certain fish chromosomes are preferentially over-represented while others are under-represented in many MPNSTs. In addition, we detected evidence for recurrent sub-chromosomal amplifications and deletions that may contain genes involved in cancer initiation or progression. One striking amplification included the c-met proto-oncogene. Our results suggest that the zebrafish may be a valuable model in which to study aneuploidy in human cancer and in which to identify candidate genes that may act as drivers in fish and potentially also in human tumors. For GSM587250-GSM587255: This Illumina sequencing data is for validation of a larger array-CGH dataset (GSM580580-GSM580621). For GSM580580-GSM580621: Two-condition (x3) experiment: (1) genomic DNA: MPNST (rp gene mutation) vs normal tail : 31 replicates; (2) MPNST (p53 mutation) vs normal tail: 5 replicates; (3) normal tail vs. normal tail (6 replicates) For GSM587250-GSM587255: Six samples total, in three pairs of tumor (MPNST) and normal tail control
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Project description:Malignant peripheral nerve sheath tumor (MPNST) development is characterized by an altered DNA methylation landscape, which presents a promising area for developing MPNST‐specific biomarkers for screening patients with NF1. Genome‐wide DNA methylation profiling of a cohort of 13 patients with MPNST (29 samples of tumor and adjacent neurofibroma tissues) and of NF1‐MPNST cell lines was performed to identify and validate candidate MPNST‐specific CpG sites (CpGs). A logistic regression prediction model was constructed to select MPNST‐specific CpGs distinct from adjacent neurofibromas and normal tissues. To test if hypermethylation at selected CpGs can also be detected in plasma from patients with MPNST, cfMBD‐seq was applied to profile the cfDNA methylome of blood from patients with MPNST and NF1. Based on stringent feature‐selection criteria and predictive modeling, we identified 73 candidate MPNST‐specific CpGs (67 with unique CpG island locations) that reliably discriminated MPNSTs from neurofibromas. Validation of five candidate biomarkers confirmed successful MPNST detection (sensitivity: > 88%, specificity: > 91%) in tissues. In plasma samples, 63 of 67 selected genomic regions had greater than 1.2‐fold higher methylation in patients with MPNST than those with NF1. Further, we identified 15 CpG islands that consistently separated plasma from patients with confirmed MPNST diagnosis from plasma of individuals with NF1 without a diagnosis of malignant transformation (FDR < 0.1). Our findings confirmed a unique hypermethylation pattern present during malignant transformation. This study highlights the potential to be further investigated further as biomarkers in clinical settings for early MPNST detection in patients with NF1.
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Project description:Malignant peripheral nerve sheath tumor (MPNST) development is characterized by an altered DNA methylation landscape, which presents a promising area for developing MPNST-specific biomarkers for screening patients with NF1. Genome-wide DNA methylation profiling of a cohort of 13 patients with MPNST (29 samples of tumor and adjacent neurofibroma tissues) and of NF1-MPNST cell lines was performed to identify and validate candidate MPNST-specific CpG sites (CpGs). A logistic regression prediction model was constructed to select MPNST-specific CpGs distinct from adjacent neurofibromas and normal tissues. To test if hypermethylation at selected CpGs can also be detected in plasma from patients with MPNST, cfMBD-seq was applied to profile the cfDNA methylome of blood from patients with MPNST and NF1. Based on stringent feature-selection criteria and predictive modeling, we identified 73 candidate MPNST-specific CpGs (67 with unique CpG island locations) that reliably discriminated MPNSTs from neurofibromas. Validation of five candidate biomarkers confirmed successful MPNST detection (sensitivity: > 88%, specificity: > 91%) in tissues. In plasma samples, 63 of 67 selected genomic regions had greater than 1.2-fold higher methylation in patients with MPNST than those with NF1. Further, we identified 15 CpG islands that consistently separated plasma from patients with confirmed MPNST diagnosis from plasma of individuals with NF1 without a diagnosis of malignant transformation (FDR < 0.1). Our findings confirmed a unique hypermethylation pattern present during malignant transformation. This study highlights the potential to be further investigated as biomarkers in clinical settings for early MPNST detection in patients with NF1.
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Project description:We utilized three murine MPNST cell lines. 67C-4 and #5NPCIS cell lines are derived from spontaneously arising tumors in mice mutated for NF1 and p53 (so-called NP-cis mice; PMID: 12154062). SN4-4 cells originated from MPNST tumors induced by injecting adenovirus containing Cas9 and guide RNA for Nf1 and p53 into the sciatic nerves, resulting in NF1/p53-null MPNST (PMID: 32456131). We implanted 5 x 10^6 murine MPNST cells, subcutaneously, into the flanks of 6-8 weeks old gender-matched C57BL/6 mice (for 67C-4 and #5NPCIS) and BALB/c mice (for SN4-4 mice) to generate MPNST tumors. All mice were procured from Envigo. Upon reaching a size of 300-500 mm3, the mice were euthanized to harvest the tumors, which were subsequently flash frozen using liquid nitrogen and processed for RNA sequencing.
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Project description:The diagnosis of Malignant peripheral nerve sheath tumors (MPNSTs) can be challenging, but is aided by their characteristic DNA methylation profile (DMP). An MPNST-like group, characterized by retained H3K27me3 expression, was recently recognized. To evaluate the diagnostic usefulness of DMP in pediatric/juvenile MPNSTs, we selected pediatric/juvenile malignancies from the Bambino Gesù Children's Hospital DMP database. DMP revealed unexpected molecular heterogeneity in histologically homogenous MPNSTs/Atypical neurofibromas, while samples with MPNST-like DMP manifested histological diversity. In conclusion, DMP is useful in diagnosing MPNST, discriminating morphologic mimics classified as MPNST in premolecular era, and investigating the MPNST-like ‘hybrid’ group in pediatrics.
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